Serotonin plays a role in several psychiatric disorders, including anxiety, Alzheimer's disease, depression, nausea and vomiting, eating disorders, and migraine. (Rasmussen et al., “Chapter 1. Recent Progress in Serotonin (5HT), Receptor Modulators”, in Annual Reports in Medicinal Chemistry, Section 1, 30, pp. 1–9, 1995, Academic Press). Serotonin also plays a role in both the positive and negative symptoms of schizophrenia. (Sharma et al., Psychiatric Annals., 26 (2), February, 1996, pp. 88–92.)
Numerous receptor subtypes have been classified according to their antagonist susceptibilities and their affinities for 5HT. The 5HT1B receptor was first identified in rats, where it has a distinct pharmacological profile. In humans, however, it shares an almost identical pharmacology with the 5HT1D receptor. In the CNS, the receptor is found in the striatum, medulla, hippocampus, frontal cortex and amygdala. In the periphery, it is found in vascular smooth muscle. The 5HT1B/5HT1D receptor may be the therapeutic substrate of the anti-migraine drug, sumatriptan; this receptor is also implicated in feeding behavior, anxiety, depression, cardiac function and movement.
Selective agonists and antagonists for 5HT1B receptors have until now been lacking, but indirect pharmacological evidence suggests that 5HT1B activation influences food intake, sexual activity, locomotion, and aggression. (Ramboz S., et al., Behav. Brain Res., 1996. 73: 305312.).
Accordingly, the compounds of the present invention are antagonists of the serotonin 5HT1B receptor, and are effective for the treatment of disorders of the serotonin system, such as depression and related disorders.